Efficacy of EZH2 inhibitory drugs in human papillomavirus-positive and human papillomavirus-negative oropharyngeal squamous cell carcinomas

Abstract

BackgroundHead and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer worldwide with rates of HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) dramatically increasing. The overexpression of enhancer of zeste homolog 2 (EZH2), a histone methyltransferase responsible for the trimethylation at lysine 27 of histone 3 (H3K27me3), is associated with a poor clinical prognosis and aggressive HPV-positive phenotypes.MethodsWe utilized three EZH2 pathway inhibitors, GSK-343, DZNeP, and EPZ-5687, and tested their efficacy in two HPV-positive and two HPV-negative OPSCC cell lines.ResultsTreatment with GSK-343 decreased H3K27me3 in all cell lines and treatment with DZNeP decreased H3K27me3 in only HPV-negative cell lines as determined by Western blot. Cells treated with EPZ-5687 displayed no appreciable change in H3K27me3. Epigenetic effect on gene expression was measured via ddPCR utilizing 11 target probes. Cells treated with DZNeP showed the most dramatic expressional changes, with decreased EGFR in HPV-positive cell lines and an overall increase in proliferation markers in HPV-negative cell lines. GSK-343-treated cells displayed moderate expressional changes, with CCND1 increased in HPV-positive cell lines and decreased TP53 in HPV-negative SCC-1. EPZ-5687-treated cell lines displayed few expressional changes overall. Only DZNeP-treated cells displayed anti-proliferative characteristics shown in wound-healing assays.ConclusionsOur findings suggest that EZH2 inhibitors are a viable therapeutic option for the role of epigenetic effect, potentially sensitizing tumors to current chemotherapies or limiting cell differentiation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-017-0390-y) contains supplementary material, which is available to authorized users.

Antitumour effects of metformin and curcumin in human papillomavirus positive and negative head and neck cancer cells

“…EGFR expression was decreased in all cell lines upon treatment with curcumin, remaining consistent with current literature, as was EZH2. Given EZH2 overexpression to be associated with overall tumor aggressiveness in both HPV+ and HPV− cancers curcumin may provide an alternate means to repressing EZH2 expression over current modalities being tested …”

“…EGFR expression was decreased in all cell lines upon treatment with curcumin, remaining consistent with current literature, 23 as was EZH2. Given EZH2 overexpression to be associated with overall tumor aggressiveness in both HPV+ and HPV− cancers 38,39 curcumin may provide an alternate means to repressing EZH2 expression over current modalities being tested. [40][41][42] Tumor-suppressor protein p53 may be the only caveat to the claim of an apparent lack of HPV discrimination in drug agents, The gene expression results of the control treatments appear to be quite variable in comparison to one another.…”

Targeting histone epigenetics to control viral infections

“… 153 It may be noted that the EZH2 inhibitor DZNep was also tested in the context of HPV-positive oropharyngeal squamous cell carcinomas, where it displayed antiproliferative characteristics, highlighting its potential use to sensitize tumors to current chemotherapies or to limit cell differentiation. 57 Taken together, manipulation of epigenetic players, with a special emphasis on HDAC inhibitors, appears to be an appealing target that could lead to enrichment of the therapeutic options array to control benign HPV infections and suppress progeny production and infectious transmission, as well as treat HPV-related dysplasia and carcinoma. This will be ensured by replicating in vitro results in predictive models and clinical trial studies with adapted experimental designs.…”

Histone modifications in oral squamous cell carcinoma and oral potentially malignant disorders

“…DZNep reduced the levels of polycomb group proteins SUZ12, BMI1 and RING1A, monoubiquitination of H2AK119, and aggressive phenotypes genes; increased epithelial phenotype genes (Hatta et al, ); caused HNSCC cell‐specific apoptosis; and induced expression of differentiation genes (Gannon et al, ). Exposure to EZH2 inhibitor GSK‐343 resulted in H3K27me3 suppression in both HPV‐positive and HPV‐negative OSCC cell lines, DZNeP in HPV‐negative cell lines, and EPZ‐5687 with no perceptible alterations, indicating that the anti‐tumorigenic activity of HMT inhibitors may be linked with HPV status (Lindsay et al, ).…”